PMID- 33116473 OWN - NLM STAT- MEDLINE DCOM- 20210625 LR - 20231213 IS - 1178-2005 (Electronic) IS - 1176-9106 (Print) IS - 1176-9106 (Linking) VI - 15 DP - 2020 TI - Mechanisms by Which the MBD2/miR-301a-5p/CXCL12/CXCR4 Pathway Regulates Acute Exacerbations of Chronic Obstructive Pulmonary Disease. PG - 2561-2572 LID - 10.2147/COPD.S261522 [doi] AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by irreversible expiratory airflow obstruction, and its chronic course is worsened by recurrent acute exacerbations. Our previous microarray assay identified microRNA (miR)-301a-5p as being associated with progression of acute exacerbation of COPD (AE-COPD); however, the mechanism underlying COPD pathogenesis remains unknown. METHODS: Samples of serum and peripheral blood mononuclear cells (PBMCs) were isolated from healthy control subjects and patients with stable COPD (R-COPD) or with an acute exacerbation of COPD (AE-COPD). Human HULEC-5a and human bronchial epithelial (HBE) cells were transfected with methyl-CpG-binding domain protein 2 (MBD2), sh-MBD2, miR-301a-5p mimics or an inhibitor, and then stimulated with cigarette smoke extract (CSE). Conditioned medium co-culture assays were performed by adding the supernatant of medium derived from HULEC-5a cells transfected with miR-301a-5p mimics or inhibitor into wells containing si-c-x-c motif chemokine receptor 4 (CXCR4)-transfected-lung fibroblasts or human leukemic THP-1 cell line macrophages. Transwell assays were performed to analyze cell migration. RESULTS: Our analysis of clinical samples showed that decreased miR-301a-5p levels in patients with AE-COPD were positively correlated with levels of MBD2 expression, but negatively correlated with levels of chemokine ligand C-X-C motif chemokine ligand 12 (CXCL12) expression. MBD2 overexpression significantly promoted miR-301a-5p production, but suppressed CXCL12 production in HULEC-5a and HBE cells. CXCL12 was confirmed to be a direct target of miR-301a-5p. CXCR4 knockdown significantly enhanced the suppressive effect of miR-301a-5p mimics and attenuated the promotional effects of the miR-301a-5p inhibitor on the migration of circulating fibroblasts and macrophages, as well as the expression levels of phospho-mitogen-activated protein kinase (p-MEK) and phospho-protein kinase B (p-AKT). CONCLUSION: In summary, the MBD2/miR-301a-5p/CXCL12/CXCR4 pathway was shown to affect the migration of lung fibroblasts and monocyte-derived macrophages, which may play an important role during COPD exacerbations. CI - (c) 2020 Shen et al. FAU - Shen, Wen AU - Shen W AD - Respiratory Department, The Second Affiliated Hospital of Kunming Medical University, Kunming, People's Republic of China. FAU - Weng, Zhiyin AU - Weng Z AD - School of Pharmaceutical Science, Kunming Medical University, Kunming, People's Republic of China. FAU - Fan, Minjuan AU - Fan M AD - Respiratory Department, The Second Affiliated Hospital of Kunming Medical University, Kunming, People's Republic of China. FAU - Wang, Shukun AU - Wang S AD - Respiratory Department, The Second Affiliated Hospital of Kunming Medical University, Kunming, People's Republic of China. FAU - Wang, Ruili AU - Wang R AD - Respiratory Department, The Second Affiliated Hospital of Kunming Medical University, Kunming, People's Republic of China. FAU - Zhang, Yang AU - Zhang Y AD - Respiratory Department, The Second Affiliated Hospital of Kunming Medical University, Kunming, People's Republic of China. FAU - Tian, Hong AU - Tian H AD - Respiratory Department, The Second Affiliated Hospital of Kunming Medical University, Kunming, People's Republic of China. FAU - Wang, Xi AU - Wang X AD - Respiratory Department, The Second Affiliated Hospital of Kunming Medical University, Kunming, People's Republic of China. FAU - Wu, Xin AU - Wu X AD - Respiratory Department, The Second Affiliated Hospital of Kunming Medical University, Kunming, People's Republic of China. FAU - Yang, Xiaolei AU - Yang X AD - Respiratory Department, The Second Affiliated Hospital of Kunming Medical University, Kunming, People's Republic of China. FAU - Wei, Wei AU - Wei W AD - Respiratory Department, The Second Affiliated Hospital of Kunming Medical University, Kunming, People's Republic of China. FAU - Yuan, Kaifen AU - Yuan K AD - Respiratory Department, The Second Affiliated Hospital of Kunming Medical University, Kunming, People's Republic of China. LA - eng PT - Journal Article DEP - 20201019 PL - New Zealand TA - Int J Chron Obstruct Pulmon Dis JT - International journal of chronic obstructive pulmonary disease JID - 101273481 RN - 0 (CXCL12 protein, human) RN - 0 (CXCR4 protein, human) RN - 0 (Chemokine CXCL12) RN - 0 (DNA-Binding Proteins) RN - 0 (MBD2 protein, human) RN - 0 (MIRN301A microRNA, human) RN - 0 (MicroRNAs) RN - 0 (Receptors, CXCR4) SB - IM MH - Chemokine CXCL12/genetics MH - DNA-Binding Proteins/metabolism MH - Humans MH - Leukocytes, Mononuclear/metabolism MH - Lung/metabolism MH - *MicroRNAs/genetics MH - *Pulmonary Disease, Chronic Obstructive/diagnosis/genetics MH - Receptors, CXCR4/genetics MH - Signal Transduction PMC - PMC7585268 OTO - NOTNLM OT - cell recruitment OT - chronic obstructive pulmonary disease OT - inflammatory chemokine OT - microRNA-301a-5p COIS- All authors declare that they have no competing interests. EDAT- 2020/10/30 06:00 MHDA- 2021/06/29 06:00 PMCR- 2020/10/19 CRDT- 2020/10/29 05:48 PHST- 2020/05/19 00:00 [received] PHST- 2020/09/23 00:00 [accepted] PHST- 2020/10/29 05:48 [entrez] PHST- 2020/10/30 06:00 [pubmed] PHST- 2021/06/29 06:00 [medline] PHST- 2020/10/19 00:00 [pmc-release] AID - 261522 [pii] AID - 10.2147/COPD.S261522 [doi] PST - epublish SO - Int J Chron Obstruct Pulmon Dis. 2020 Oct 19;15:2561-2572. doi: 10.2147/COPD.S261522. eCollection 2020.